EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer
Guan-Yu Xiao, Xiaochao Tan, B. Leticia Rodriguez, Don L. Gibbons, Shike Wang, Chao‐Liang Wu, Xin Liu, Yu Jiang, Mayra E. Vasquez, Hai T. Tran, Jun Xu, William K. Russell, Cara Haymaker, Younghee Lee, Jianjun Zhang, Luisa M. Solis, Ignacio I. Wistuba, Jonathan M. Kurie
Abstract
Epithelial-to-mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT-activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8 + T cell exhaustion, indicating that cell-intrinsic and extrinsic processes are linked through a microRNA that coordinates vesicular trafficking networks. Blockade of ZEB1-dependent secretion reactivates antitumor immunity and negates resistance to PD-L1 immune checkpoint blockade, an important clinical problem in LUAD. Thus, EMT activates exocytotic Rabs to drive a secretory program that promotes invasion and immunosuppression in LUAD.